Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth

• Published in: Journal of experimental & clinical cancer research Vol. 42; no. 1; p. 25
• Main Authors: Keller, Magdalena, Rohlf, Katharina, Glotzbach, Annika, Leonhardt, Gregor, Lüke, Simon, Derksen, Katharina, Demirci, Özlem, Göçener, Defne, AlWahsh, Mohammad, Lambert, Jörg, Lindskog, Cecilia, Schmidt, Marcus, Brenner, Walburgis, Baumann, Matthias, Zent, Eldar, Zischinsky, Mia-Lisa, Hellwig, Birte, Madjar, Katrin, Rahnenführer, Jörg, Overbeck, Nina, Reinders, Jörg, Cadenas, Cristina, Hengstler, Jan G, Edlund, Karolina, Marchan, Rosemarie
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20-01-2023; BioMed Central; BMC
• Subjects: Antibodies; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Care and treatment; Cell Line, Tumor; Cells; Choline; Choline - metabolism; Choline - therapeutic use; Drug Resistance, Neoplasm - genetics; Female; Gene expression; Genes; GPCPD1; Growth; HER2 positive breast cancer; HER2-targeting therapy resistance; Humans; Immunohistochemistry; Metabolism; Metabolites; Monoclonal antibodies; NMR; Nuclear magnetic resonance; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipases - genetics; Physiological aspects; Protein expression; Proteins; Receptor, ErbB-2 - metabolism; RNA; RNA, Small Interfering; Scientific equipment and supplies industry; Tyrosine; Viral antibodies; United States; Breast cancer; GPCPD1; HER2 positive breast cancer; HER2-targeting therapy resistance; Choline metabolism
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-022-02578-w

Intrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored.
EDI3 mRNA and protein expression in human breast cancer tissue were investigated using publicly-available Affymetrix gene expression microarray datasets (n = 540) and with immunohistochemistry on a tissue microarray (n = 265), respectively. A panel of breast cancer cell lines of different molecular subtypes were used to investigate expression and activity of EDI3 in vitro. To determine whether EDI3 expression is regulated by HER2 signalling, the effect of pharmacological inhibition and siRNA silencing of HER2, as well as the influence of inhibiting key components of signalling cascades downstream of HER2 were studied. Finally, the influence of silencing and pharmacologically inhibiting EDI3 on viability was investigated in vitro and on tumour growth in vivo.
In the present study, we show that EDI3 expression is highest in ER-HER2 + human breast tumours, and both expression and activity were also highest in ER-HER2 + breast cancer cell lines. Silencing HER2 using siRNA, as well as inhibiting HER2 signalling with lapatinib decreased EDI3 expression. Pathways downstream of PI3K/Akt/mTOR and GSK3β, and transcription factors, including HIF1α, CREB and STAT3 were identified as relevant in regulating EDI3 expression. Silencing EDI3 preferentially decreased cell viability in the ER-HER2 + cells. Furthermore, silencing or pharmacologically inhibiting EDI3 using dipyridamole in ER-HER2 + cells resistant to HER2-targeted therapy decreased cell viability in vitro and tumour growth in vivo.
Our results indicate that EDI3 may be a potential novel therapeutic target in patients with HER2-targeted therapy-resistant ER-HER2 + breast cancer that should be further explored.